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Loss of the importin Kpna2 causes infertility in male maice by disrupting the translocation of testis-specific transcription factors

ABSTRACT: Karyopherin proteins mediate the movement between the nucleus and cytoplasm of specific proteins that are essential for spermatogenesis. Through a loss-of-function approach, we here examine the specific role of Karyopherin Subunit Alpha 2 (Kpna2) in spermatogenesis and male fertility. The factors determined were (i) the spatial distribution of KPNA2 in the testis using immunofluorescence; (ii) the morphological and functional consequences of Kpna2 deficiency in terms of sperm production, quality, and motility, and fertility in knock-out and wild-type mice; and (iii) the transcriptomic consequences of Kpna2 deficiency in knock-out compared to wild-type mice by RNA-seq analysis. KPNA2 was found expressed in the cytoplasm of primary spermatocytes and the nucleus and cytoplasm of secondary spermatocytes and spermatid cells. Ablation of Kpna2 in male mice reduced their size, affected sperm motility, increased sperm abnormalities, and led to dysregulation of testis gene expression and ultimately to infertility. Impaired mRNA expression mainly affected clusters of genes expressed in spermatids and spermatocytes. Downregulated genes include a set of genes that participate in cell adhesion, extracellular matrix (ECM) organization, and ECM-receptor interaction. We detected the enrichment of some transcription factors that bind to regions around transcription start sites of downregulated genes. We propose an essential role of Kpna2 in spermatogenesis via the disrupted translocation of testis specific transcription factors that control the expression of genes related to ECM organization in the seminiferous tubules.

ORGANISM(S): Mus musculus

PROVIDER: GSE213442 | GEO | 2023/07/19

REPOSITORIES: GEO

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Project description:The specific role of polyamines in the testis physiology is not fully understood. Antizymes (OAZs) and antizyme inhibitors (AZINs) are modulators of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis and polyamine uptake. Although the three known OAZs are expressed in the testis, only OAZ3 is testis specific and has been proven to have an essential role in male fertility. Regarding the two existing AZINs, AZIN2 is the most abundantly expressed member in this gonad. Whereas previous studies suggested that AZIN2 might participate in mouse spermatogenesis, immunohistological analysis of human testicular sections revealed that AZIN2 is also detected in the steroidogenic Leydig cells but not in the germinal epithelium. In the present study, we found a close ontogenic similarity in the mRNA levels of OAZs and AZINs between mice and rats, but an opposite expression pattern of ODC activity. Further analysis of AZIN2 and OAZ3 in the testis of mice with different alterations in spermatogenesis and fertility, induced either genetically or pharmacologically, corroborated that both AZIN2 and OAZ3 are mainly expressed in the haploid germinal cells. Finally, by using transgenic mice with a truncated Azin2 gene fused to the bacterial lacZ gene, we studied the expression of Azin2 in testes, epididymides and spermatozoa. AZIN2 was detected in spermatids and spermatozoa, as well as in Leydig cells, and in epithelial epidydimal cells. Azin2 knock-out male mice were fertile; however, they showed marked decreases in testicular putrescine and plasma and testicular testosterone levels, and a dramatic reduction in the sperm motility. These results suggest an important role for AZIN2 in testicular cells by modulating polyamine concentrations, testosterone synthesis and sperm function. Overall, our data corroborate the relevance of polyamine regulation in spermatogenesis, where both AZIN2 and OAZ3 play fundamental roles. We used microarrays in order to detect how the disruption of Azin2 could affect overall gene expression in testis.

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Loss of the importin Kpna2 causes infertility in male maice by disrupting the translocation of testis-specific transcription factors

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